The role of NLRC4 and ASC in recognition and control of infection with Leishmania (L.) amazonensis.

Abstract

Leishmaniasis is a group of diseases caused by protozoa of Leishmania genus. These parasites exhibit a remarkable capacity to survive and proliferate within the phagolysosome of host macrophages. Macrophages express different pattern recognition receptors (PRR) such as Toll-like receptors (TLRs) and Nod-like receptors (NLRs). These PRRs recognize molecular patterns associated with pathogens (PAMPs) and trigger intracellular signaling pathways leading to the production of cytokines and other inflammatory mediators, responsible to eliminate pathogens. Among NLRs, stand out Nod1, Nod2 and other proteins which participate in inflammasome formation, such as NLRP1, NLRP3, and NLRC4. The inflammasome is able to activate caspase-1. Activated-caspase-1 is responsible for processing and secrete IL-1² and IL-18, as well as to induce cellular pyroptotic death. The signaling of NLRP3 and NLRP1 inflammasomes is dependent on the adapter protein ASC, while the NLRC4 inflammasome seems to be independent of ASC. While many publications emphasize the importance of TLRs in the susceptibility and control of Leishmania infection, the role of NLRs is still unclear. Data from our group suggest an important participation of NLRP3 and ASC to control the replication of Leishmania in mice (data submitted for publication). Additionally, preliminary studies suggest that NLRC4 protein also appears to participate in this process (see preliminary data). Therefore, the aim of this research project is to analyze the participation and activation of NLRC4 inflammasome in L. amazonensis infection in vitro and in vivo.